The haemostatic system is responsible for maintaining circulatory fluidity and for preventing haemorrhage in response to vascular injury. Physiological hemostasis is controlled by mechanisms of coagulation and the formation of fibrin and by those favouring the degradation of fibrin (fibrinolysis).
Hyperfibrinolytic states caused by congenital or acquired conditions predispose to important haemorrhagic complications, often requiring transfusions and the need for re-exploration having a detrimental effect on patient outcome. Hemorhage is responsible for almost 50% of deaths occurring within 24 hours of traumatic injury and for up to 80% of intraoperative trauma mortality. In western countries about one third of in-hospital deaths due to trauma is caused by abnormal blood loss which is an important contributory factor for other causes of death, particularly multi-organ failure, requiring massive blood transfusion. Failure to start appropriate early management in bleeding trauma patients is a leading cause of preventable death from trauma. Post-partum hemorrhage (PPH) is another leading cause of death in the developing world, accounting for 25% of maternal deaths, and rose in the developed world from 1.5% in 1999 to 4.1% in 2009. The risk of haemorrhage can also be important in cardiovascular patients on anti-coagulant therapy. Pharmacological approaches are an important part of multimodal therapy aiming to reducing bleeding and transfusion in order to reverse specific defects associated with such states; among them, the role of fibrinolysis inhibitors is growing.
It is well known that subjects who bleed excessively in association with surgery or major trauma and need blood transfusions develop more complications than those who do not experience any bleeding. However, moderate bleeding requiring the administration of human blood products may lead to complications associated with the risk of transferring human viruses. Extensive bleeding requiring massive blood transfusions may lead to the development of multiple organ failure including lung or kidney function. Therefore, a major goal in surgery as well as in the treatment of major tissue damage is to avoid or minimise bleeding in order to ensure the formation of stable and solid haemostatic plugs that are not easily dissolved by fibrinolytic enzymes. Furthermore, it is of importance to ensure quick and effective formation of such plugs or clots.
Antifibrinolytic agents are widely used in major surgery to prevent fibrinolysis and reduce blood loss. Currently two synthetic lysine analogs, epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA), are the only antifibrinolytics commercially available to control bleeding. These agents competitively inhibit activation of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen and other plasma proteins. However, there are some concerns with these currently available antifibrinolytic agents due to the potential risk of thrombotic complications.
There is still a need for improved treatment of subjects experiencing bleeding episodes, including subjects where the bleeding episodes are due to surgery, trauma, or other forms of tissue damage, as well as in clinical scenarios characterized by excessive fibrinolysis.